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Characterization of Effect of Repeated Bolus or Continuous Intrathecal Infusion of Morphine on Spinal Mass Formation
Keith R Hildebrand1, Linda M Page1, Tina M Billstrom2
1Medtronic, Restorative Therapies Group, Targeted Drug Delivery, Minneapolis, MN, USA.
Background:
We determined whether intrathecally delivering the same daily dose of morphine (MS) at a fixed concentration of 25 mg/mL by periodic boluses versus continuous infusion would reduce intrathecal mass (IMs) formation in dogs.
Methods:
Adult dogs (hound cross, n = 32) were implanted with intrathecal catheters connected to SynchroMed II infusion pumps. Animals were randomly assigned to receive infusion of 0.48 mL/day of saline or MS dosing (12 mg/day at 25 mg/mL) as boluses: x1 (q24hour), x2 (q12hour), x4 (q6hour), or x8 (q3hour) given at the rate of 1000 μL/hour, or as a continuous infusion (25 mg/mL/20 μL/hour).
Results:
With IT saline, minimal pathology was noted. In contrast, animals receiving morphine displayed spinally compressing durally derived masses with the maximal cross-sectional area being greatest near the catheter tip. Histopathology showed that IMs consisted of fibroblasts in a collagen (type 1) matrix comprised of newly formed collagen near the catheter and mature collagen on the periphery of the mass. The rank order of median cross-sectional mass area (mm2 ) was: Saline: 0.7 mm2 ; x2: 1.8 mm2 ; x4: 2.7 mm2 ; x1: 2.7 mm2 ; x8: 4.2 mm2 ; Continuous: 8.1 mm2 , with statistical difference from saline being seen with continuous (p < 0.0001) and x8 (p < 0.05). Bench studies with a 2D diffusion chamber confirmed an increase in dye distribution and lower peak concentrations after bolus delivery versus continuous infusion of dye.
Conclusions:
Using multiple bolus dosing, IMs were reduced as compared to continuous infusion, suggesting relevance of bolus delivery in yielding reduced intrathecal masses.
Insights
Periodic bolus delivery of morphine reduced intrathecal masses (IMs) compared to continuous infusion in dogs. This suggests bolus dosing may be a strategy to minimize IMs in patients receiving intrathecal therapy.
Area of Science:
- Neuroscience
- Pharmacology
- Biomedical Engineering
Background:
- Intrathecal drug delivery systems are used for pain management.
- Morphine delivery via intrathecal infusion can lead to the formation of intrathecal masses (IMs).
- The impact of different delivery methods (bolus vs. continuous) on IM formation is not fully understood.
Purpose of the Study:
- To investigate whether periodic bolus delivery of morphine reduces intrathecal mass (IM) formation compared to continuous infusion.
- To compare the efficacy of different bolus frequencies (1, 2, 4, or 8 times daily) in mitigating IMs.
Main Methods:
- Adult dogs received intrathecal catheters and infusion pumps.
- Animals were administered saline or morphine (12 mg/day) via continuous infusion or periodic boluses (1, 2, 4, or 8 times daily).
- Intrathecal mass size was quantified, and histopathology was performed.
Main Results:
- Continuous morphine infusion resulted in significantly larger IMs (8.1 mm²) compared to saline (0.7 mm²).
- Multiple bolus deliveries (especially 8 times daily) showed reduced IM size compared to continuous infusion.
- Bench studies confirmed lower peak concentrations and wider distribution with bolus dye delivery.
Conclusions:
- Periodic bolus delivery of morphine significantly reduces intrathecal mass formation compared to continuous infusion.
- Bolus dosing strategies may be beneficial in minimizing IMs associated with intrathecal morphine therapy.
- These findings have implications for optimizing intrathecal drug delivery regimens.
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